Honors & Awards
Merck Research Laboratories Fellowship, Life Science Research Foundation (August 2015-date)
Long-Term Fellowship, EMBO (February 2013-August 2014)
Bachelor of Science, University of Manchester (2007)
Doctor of Philosophy, University College London (2012)
Ben Barres, Postdoctoral Faculty Sponsor
Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse
2016; 89 (1): 37-53
The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.
View details for DOI 10.1016/j.neuron.2015.11.013
View details for Web of Science ID 000373564300006
View details for PubMedID 26687838
Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture.
2015; 12 (7): 671-678
The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro.
View details for DOI 10.1038/nmeth.3415
View details for PubMedID 26005811
- Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways NATURE 2013; 504 (7480): 394-?
Glia keep synapse distribution under wraps.
2013; 154 (2): 267-268
The wiring of the nervous system requires that axons navigate to the correct targets and maintain their correct positions during developmental growth. In this issue, Shao et al. (2013) now reveal a crucial new role for glia in preserving correct synaptic connectivity during developmental growth.
View details for DOI 10.1016/j.cell.2013.06.045
View details for PubMedID 23870116
- Emerging roles of astrocytes in neural circuit development (vol 14, pg 311-321, 2013) NATURE REVIEWS NEUROSCIENCE 2013; 14 (6): 443-443
Emerging roles of astrocytes in neural circuit development
NATURE REVIEWS NEUROSCIENCE
2013; 14 (5): 311-321
Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.
View details for DOI 10.1038/nrn3484
View details for Web of Science ID 000317913900008
View details for PubMedID 23595014
Properties and Fate of Oligodendrocyte Progenitor Cells in the Corpus Callosum, Motor Cortex, and Piriform Cortex of the Mouse
JOURNAL OF NEUROSCIENCE
2012; 32 (24): 8173-8185
Oligodendrocyte progenitor cells (OPCs) in the postnatal mouse corpus callosum (CC) and motor cortex (Ctx) reportedly generate only oligodendrocytes (OLs), whereas those in the piriform cortex may also generate neurons. OPCs have also been subdivided based on their expression of voltage-gated ion channels, ability to respond to neuronal activity, and proliferative state. To determine whether OPCs in the piriform cortex have inherently different physiological properties from those in the CC and Ctx, we studied acute brain slices from postnatal transgenic mice in which GFP expression identifies OL lineage cells. We whole-cell patch clamped GFP-expressing (GFP(+)) cells within the CC, Ctx, and anterior piriform cortex (aPC) and used prelabeling with 5-ethynyl-2'-deoxyuridine (EdU) to assess cell proliferation. After recording, slices were immunolabeled and OPCs were defined by strong expression of NG2. NG2(+) OPCs in the white and gray matter proliferated and coexpressed PDGFR? and voltage-gated Na(+) channels (I(Na)). Approximately 70% of OPCs were capable of generating regenerative depolarizations. In addition to OLIG2(+) NG2(+) I(Na)(+) OPCs and OLIG2(+) NG2(neg) I(Na)(neg) OLs, we identified cells with low levels of NG2 limited to the soma or the base of some processes. These cells had a significantly reduced I(Na) and a reduced ability to incorporate EdU when compared with OPCs and probably correspond to early differentiating OLs. By combining EdU labeling and lineage tracing using Pdgfr?-CreER(T2) : R26R-YFP transgenic mice, we double labeled OPCs and traced their fate in the postnatal brain. These OPCs generated OLs but did not generate neurons in the aPC or elsewhere at any time that we examined.
View details for DOI 10.1523/JNEUROSCI.0928-12.2012
View details for Web of Science ID 000305295600009
View details for PubMedID 22699898
- An astrocyte TRP switch for inhibition. Nature neuroscience 2012; 15 (1): 3-4
Dorsally and Ventrally Derived Oligodendrocytes Have Similar Electrical Properties but Myelinate Preferred Tracts
JOURNAL OF NEUROSCIENCE
2011; 31 (18): 6809-6819
In the developing spinal cord, most oligodendrocyte precursors (OLPs) arise from the ventral ventricular zone (VZ) under the influence of Sonic Hedgehog, but a minority are generated from the dorsal VZ in a Hedgehog-independent manner. In the developing forebrain too, OLPs arise from both the ventral and the dorsal VZ. It is not known whether dorsally and ventrally derived oligodendrocyte (OL) lineage cells have different properties. We generated a dual reporter mouse line to color code ventrally and dorsally derived OLPs (vOLPs and dOLPs) and their differentiated oligodendrocyte progeny (vOLs and dOLs) for functional studies. We found that ?80% of OL lineage cells in the postnatal spinal cord and ?20% in the corpus callosum are ventrally derived. In both spinal cord and corpus callosum, vOLPs and dOLPs had indistinguishable electrical properties, as did vOLs and dOLs. However, vOLPs and dOLPs had different migration and settling patterns. In the spinal cord, vOLPs appeared early and spread uniformly throughout the cord, whereas dOLPs arrived later and remained mainly in the dorsal and dorsolateral funiculi. During adulthood, corticospinal and rubrospinal tracts became myelinated mainly by dOLs, even though vOLs dominated these tracts during early postnatal life. Thus, dOLPs are electrically similar to vOLPs but appear to outcompete them for dorsal axons.
View details for DOI 10.1523/JNEUROSCI.6474-10.2011
View details for Web of Science ID 000290212100023
View details for PubMedID 21543611
Conserved site for neurosteroid modulation of GABA(A) receptors
2009; 56 (1): 149-154
This study addresses whether the potentiation site for neurosteroids on GABA(A) receptors is conserved amongst different GABA(A) receptor isoforms. The neurosteroid potentiation site was previously identified in the alpha1beta2gamma2S receptor by mutation of Q241 to methionine or leucine, which reduced the potentiation of GABA currents by the naturally occurring neurosteroids, allopregnanolone or tetrahydrodeoxycorticosterone (THDOC). By using heterologous expression of GABA(A) receptors in HEK cells, in combination with whole-cell patch clamp recording methods, a relatively consistent potentiation by allopregnanolone of GABA-activated currents was evident for receptors composed of one alpha subunit isoform (alpha2-5) assembled with beta3 and gamma2S subunits. Using mutant alphabetagamma receptors, the neurosteroid potentiation was universally dependent on the conserved glutamine residue in M1 of the respective alpha subunit. Studying wild-type and mutant receptors composed of alpha4beta3delta subunits revealed that the delta subunit is unlikely to contribute to the neurosteroid potentiation binding site and probably affects the efficacy of potentiation. Thus, in keeping with the ability of neurosteroids to potentiate GABA currents via a broad variety of GABA(A) receptor isoforms in neurons, the potentiation site is structurally highly conserved on this important neurotransmitter receptor family.
View details for DOI 10.1016/j.neuropharm.2008.07.050
View details for Web of Science ID 000262625500017
View details for PubMedID 18762201